GLP-2 Is Locally Produced From Human Islets and Balances Inflammation Through an Inter-Islet-Immune Cell Crosstalk

Front Endocrinol (Lausanne). 2021 Jul 5;12:697120. doi: 10.3389/fendo.2021.697120. eCollection 2021.


Glucagon-like peptide-1 (GLP-1) shows robust protective effects on β-cell survival and function and GLP-1 based therapies are successfully applied for type-2 diabetes (T2D) and obesity. Another cleavage product of pro-glucagon, Glucagon-like peptide-2 (GLP-2; both GLP-1 and GLP-2 are inactivated by DPP-4) has received little attention in its action inside pancreatic islets. In this study, we investigated GLP-2 production, GLP-2 receptor (GLP-2R) expression and the effect of GLP-2R activation in human islets. Isolated human islets from non-diabetic donors were exposed to diabetogenic conditions: high glucose, palmitate, cytokine mix (IL-1β/IFN-γ) or Lipopolysaccharide (LPS) in the presence or absence of the DPP4-inhibitor linagliptin, the TLR4 inhibitor TAK-242, the GLP-2R agonist teduglutide and/or its antagonist GLP-2(3-33). Human islets under control conditions secreted active GLP-2 (full-length, non-cleaved by DPP4) into the culture media, which was increased by combined high glucose/palmitate, the cytokine mix and LPS and highly potentiated by linagliptin. Low but reproducible GLP-2R mRNA expression was found in all analyzed human islet isolations from 10 donors, which was reduced by pro-inflammatory stimuli: the cytokine mix and LPS. GLP-2R activation by teduglutide neither affected acute or glucose stimulated insulin secretion nor insulin content. Also, teduglutide had no effect on high glucose/palmitate- or LPS-induced dysfunction in cultured human islets but dampened LPS-induced macrophage-dependent IL1B and IL10 expression, while its antagonist GLP-2(3-33) abolished such reduction. In contrast, the expression of islet macrophage-independent cytokines IL6, IL8 and TNF was not affected by teduglutide. Medium conditioned by teduglutide-exposed human islets attenuated M1-like polarization of human monocyte-derived macrophages, evidenced by a lower mRNA expression of pro-inflammatory cytokines, compared to vehicle treated islets, and a reduced production of itaconate and succinate, marker metabolites of pro-inflammatory macrophages. Our results reveal intra-islet production of GLP-2 and GLP-2R expression in human islets. Despite no impact on β-cell function, local GLP-2R activation reduced islet inflammation which might be mediated by a crosstalk between endocrine cells and macrophages.

Keywords: GLP-2; GLP-2R; alpha-cell; beta-cell; diabetes; inflammation; islets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication / drug effects
  • Cell Communication / physiology
  • Cells, Cultured
  • Female
  • Glucagon-Like Peptide 2 / metabolism*
  • Glucagon-Like Peptide-2 Receptor / genetics
  • Glucagon-Like Peptide-2 Receptor / metabolism
  • Homeostasis / drug effects
  • Humans
  • Immune System / drug effects
  • Immune System / physiology
  • Inflammation* / chemically induced
  • Inflammation* / immunology
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / pathology
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Lipopolysaccharides
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Male
  • Pancreatitis / immunology
  • Pancreatitis / metabolism
  • Pancreatitis / pathology


  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-2 Receptor
  • Lipopolysaccharides